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Pharmacokinetics and Safety of PA-824 in Subjects With Mild, Moderate, and Severe Hepatic Impairment to Matched, Non-Hepatically Impaired Subjects

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ClinicalTrials.gov Identifier: NCT02422524
Recruitment Status : Recruiting
First Posted : April 21, 2015
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This is a Phase 1, single dose (200 mg), open-label, sequential group study comparing the pharmacokinetics and safety of PA-824 in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 1 VTEU site, study duration is approximately 15 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of PA-824 in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of PA-824 in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.

Condition or disease Intervention/treatment Phase
Tuberculosis Drug: PA-824 Phase 1

Detailed Description:
This is a Phase 1, single dose (200 mg), open-label, sequential group study comparing the pharmacokinetics and safety of PA-824 in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. This study will enroll approximately 6 subjects with mild hepatic impairment (Child-Pugh A), approximately 6 subjects with moderate hepatic impairment (Child-Pugh B), approximately 6 subjects with severe hepatic impairment (Child-Pugh C), and approximately 18 matched non-hepatically impaired subjects. Non-hepatically impaired subjects in the control group will be matched to subjects with hepatic impairment based on age (+/- 10 years) and body weight (+/- 20%) as measured at screening (Visit 00A). There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 1 VTEU site, study duration is approximately 15 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of PA-824 in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of PA-824 in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Single Dose, Open-Label, Sequential Group Study Comparing the Pharmacokinetics and Safety of PA-824 in Subjects With Mild, Moderate, and Severe Hepatic Impairment to Matched, Non-Hepatically Impaired Subjects
Actual Study Start Date : December 11, 2017
Estimated Primary Completion Date : December 11, 2019
Estimated Study Completion Date : December 11, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Child-Pugh A (Mild hepatic impairment)
6 Subjects will receive a single oral dose of 200mg PA-824 tablets on day 1
Drug: PA-824
PA-824 is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg PA-824 on day 1.

Experimental: Child-Pugh B (Moderate hepatic impairment)
6 Subjects will receive a single oral dose of 200mg PA-824 tablets on day 1
Drug: PA-824
PA-824 is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg PA-824 on day 1.

Experimental: Child-Pugh C (Severe hepatic impairment)
6 Subjects will receive a single oral dose of 200mg PA-824 tablets on day 1
Drug: PA-824
PA-824 is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg PA-824 on day 1.

Experimental: Non-hepatically impaired controls
18 matched Subjects will receive a single oral dose of 200mg PA-824 tablets on day 1
Drug: PA-824
PA-824 is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg PA-824 on day 1.




Primary Outcome Measures :
  1. AUC(0-infinity): Area under the concentration time-curve extrapolated to infinity at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]
  2. AUC(0-last): Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]
  3. CL/F: Apparent oral clearance calculated from Dose/AUC(0-infinifty) at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]
  4. Cmax: Maximum PA-824 concentration at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]
  5. t(1/2): Apparent terminal elimination half-life at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]
  6. Tmax: Time of maximum PA-824 concentration at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]
  7. Vd/F: Apparent Volume of Distribution at specified pre-dose and post-dose time points [ Time Frame: Day 1 to Day 5 ]

Secondary Outcome Measures :
  1. Incidence of related adverse events [ Time Frame: Day 1 to Day 12 ]
  2. Incidence of serious adverse events [ Time Frame: Day 1 to Day 12 ]
  3. Severity of related adverse events [ Time Frame: Day 1 to Day 12 ]
  4. Severity of serious adverse events [ Time Frame: Day 1 to Day 12 ]
  5. Summary of ECG data [ Time Frame: Day -1 and Day 12 ]
  6. Summary of physical examination findings (height at baseline, and weight at serial time points) [ Time Frame: Day -1 to Day 12 ]
  7. Summary of safety laboratory parameters [ Time Frame: Day -1, 2, 5, and 12 ]
  8. Summary of vital signs at serial time points [ Time Frame: Day -1 to Day 12 ]


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3):

  1. Subject is able to give voluntary written informed consent before any study related procedure is performed.
  2. 18-70 years of age, inclusive.
  3. Acceptable laboratory values* obtained at screening (within 21 days prior to admission to the DEPRU) and at admission to the DEPRU.

    • Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and urinalysis deemed not clinically significant by the investigator.
  4. Hepatic impairment classified as Child-Pugh class A (mild), B (moderate), or C (severe) criteria at screening for Groups 1, 2, or 3, respectively, and documented evidence of hepatic cirrhosis*.

    • by biopsy, nuclear scan, CT, MRI, ultrasound, or other clinically acceptable methods
  5. If female, not of childbearing potential* or agrees to avoid becoming pregnant by using acceptable contraception** during the duration of the study.

    *Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy or status after hysterectomy.

    **Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual intercourse with men.

  6. If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after dosing by using an acceptable method of birth control*.

    • In addition to the use of a barrier method (condom) even if vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #5, and abstinence from sexual intercourse with women.
  7. If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy test at admission to DEPRU.
  8. Willingness to comply with all protocol requirements.

Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4):

  1. Subject is able to give voluntary written informed consent before any study related procedure is performed.
  2. 18-70 years of age, inclusive.
  3. Subject is a healthy volunteer as determined by no clinically significant findings from medical history, physical examination, vital signs, and 12-lead ECG as determined by the Site Investigator.
  4. Acceptable laboratory values* obtained at screening (within 21 days prior to admission to the DEPRU) and at admission to the DEPRU.

    *Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and urinalysis within the reference range for the test laboratory, unless deemed not clinically significant by the investigator.

  5. If female, not of childbearing potential* or agrees to avoid becoming pregnant by using acceptable contraception** during the duration of the study.

    *Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy or status after hysterectomy.

    **Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual intercourse with men.

  6. If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after dosing by using an acceptable method of birth control*.

    *In addition to the use of a barrier method (condom) even if vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #5, and abstinence from sexual intercourse with women.

  7. If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy test at admission to DEPRU.
  8. Willingness to comply with all protocol requirements.

Exclusion Criteria:

Exclusion Criteria for Patients with Hepatic Impairment (Groups 1-3):

  1. Hypokalemia (< 3.5mEq/L), severe hypomagnesemia (< 1.1 mg/dL) or severe hypocalcemia (< 7.5 mg/dL).
  2. AST or ALT > 10 times the upper limit of normal.
  3. Creatinine clearance < 60 ml/min.
  4. Inability to swallow tablets.
  5. Presence of any condition or finding* which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments**.

    *in the opinion of the site investigator

    **e.g., inability to draw PK samples

  6. History of fever or documented fever (oral temperature > / = 100.4 degrees F or > / = 38.0 degrees C) in the 48 hours prior to admission to the DEPRU.
  7. Currently breastfeeding.
  8. History of chronic tobacco/nicotine use (> 10 cigarettes per day for 3 months minimum prior to DEPRU admission).
  9. History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole and related substances and azole antifungals or aromatase inhibitors).
  10. Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to screening.
  11. Use of any over the counter (OTC) medication* within 7 days prior to admission to the DEPRU, unless** the substance would not likely impact the validity of the study results.

    *including vitamins and herbal supplements, cough and cold medications.

    **in the opinion of the site investigator

  12. Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the DEPRU, unless** the substance would not likely impact the validity of the study results.

    *except hormonal contraceptives

    **in the opinion of the site investigator NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications section.

  13. Treatment with any drugs* known to prolong the electrocardiographic QT interval within 15 days prior to admission to the DEPRU.

    *Including excessive chronic caffeine (> six 8 oz cups of brewed coffee daily or > 3 energy drinks daily), theophylline (> 600 mg/day), or ephedrine (> 300 mg/day) use.

  14. A positive blood screen for HIV.
  15. A positive alcohol breath test or a urine screen test for drugs of abuse* at screening and at admission to the DEPRU.

    • Amphetamines, barbiturates, cocaine metabolites, marijuana, opiates, phencyclidine (PCP).

    NOTE: Results of the urine screen test can be ignored if in the opinion of the PI the results can be explained by the concomitant medications history.

  16. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, weight lifting, competitive sports) during the course of the study.
  17. Consumption of grapefruit juice in the 48 hours before admission to the DEPRU, or the inability to abstain from these until completion of Day 12.
  18. A QTcF interval > 440 msec (males) or > 450 msec (females) at screening (Visit 00A) or admission to the DEPRU (Visit 00B) or a history of prolonged QTc interval.
  19. A family history* of Long QT Syndrome, premature cardiac death**, or sudden death without a preceding diagnosis of a condition*** that could be causative of sudden death.

    • parents **due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women) ***such as known coronary artery disease, congestive heart failure, or terminal cancer
  20. Any clinically significant ECG abnormality, in the opinion of the site investigator, at screening and at admission to the DEPRU.
  21. Donation of > 500 mL blood within the 30 days prior to admission to the DEPRU.
  22. Plans to donate blood during the study or up to 14 days after dosing.

Exclusion Criteria for Non-Hepatically Impaired Controls (Group 4):

  1. Inability to swallow tablets.
  2. Presence of any condition or finding* which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments**.

    *in the opinion of the site investigator

    **e.g., inability to collect PK samples

  3. History of fever or documented fever (oral temperature > / = 100.4 degrees F or > / = 38.0 degrees C) in the 48 hours prior to admission to the DEPRU.
  4. Currently breastfeeding.
  5. History of chronic tobacco/nicotine use (> 10 cigarettes per day for 3 months minimum prior to DEPRU admission).
  6. History of seizures (other than febrile seizures during childhood) or known or suspected CNS disorders that may predispose to seizures.
  7. History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole and related substances and azole antifungals or aromatase inhibitors).
  8. Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to screening.
  9. Use of any over the counter (OTC) medication* within 7 days prior to admission to the DEPRU, unless** the substance would not likely impact the validity of the study results.

    *including vitamins and herbal supplements, antacids, cough and cold medications.

    • in the opinion of the site investigator
  10. Use of prescription medication except hormonal contraceptives within 30 days prior to admission to the DEPRU, unless* the substance would not likely impact study result validity.

    *in the opinion of the site investigator

  11. Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the DEPRU, unless** the substance would not likely impact the validity of the study results.

    *except hormonal contraceptives

    **in the opinion of the site investigator NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications section.

  12. Treatment with any drugs* known to prolong the electrocardiographic QT interval within 15 days prior to admission to the DEPRU.

    *Including excessive chronic caffeine (> six 8 oz cups of brewed coffee daily or > 3 energy drinks daily), theophylline (> 600 mg/day), or ephedrine (> 300 mg/day) use.

  13. A positive blood screen for HIV.
  14. A positive blood screen for hepatitis B surface antigen (HBsAg), or hepatitis C antibody.
  15. A positive alcohol breath test (or other suitable test for alcohol) or a urine screen test for drugs of abuse* at screening and at admission to the DEPRU.

    *Amphetamines, barbiturates, benzodiazepines, cocaine metabolites, marijuana, opiates, phencyclidine (PCP).

  16. A history of alcohol abuse or dependence within the past 1 month prior to admission to the DEPRU.
  17. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, weight lifting, competitive sports) during the course of the study.
  18. Consumption of grapefruit juice in the 48 hours before admission to the DEPRU, or the inability to abstain from these until completion of Day 12.
  19. A QTcF interval > 440 msec (males) or > 450 msec (females) at screening (Visit 00A) or admission to the DEPRU (Visit 00B) or a history of prolonged QTc interval.
  20. A family history* of Long QT Syndrome, premature cardiac death**, or sudden death without a preceding diagnosis of a condition*** that could be causative of sudden death.

    *parents

    **due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women)

    ***such as known coronary artery disease, congestive heart failure, or terminal cancer

  21. Any clinically significant ECG abnormality, in the opinion of the site investigator, at screening and at admission to the DEPRU.
  22. Donation of > 500 mL of blood within the 30 days prior to admission to the DEPRU.
  23. Plans to donate blood during the study or up to 14 days after dosing.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02422524


Contacts
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Contact: Julius Wilder 19196848111 julius.wilder@dm.duke.edu

Locations
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United States, North Carolina
Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit Recruiting
Durham, North Carolina, United States, 27710-4000
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02422524     History of Changes
Other Study ID Numbers: 13-0053
HHSN272201300017I
First Posted: April 21, 2015    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Hepatic
impairment
PA-824
Pharmacokinetics
Safety
Tuberculosis

Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections